There is limited understanding of the role of host metabolism in the pathophysiology of human tuberculosis (TB). Using high resolution metabolomics with an unbiased approach to metabolic pathway analysis, we discovered that the tryptophan pathway is highly regulated throughout the spectrum of TB infection and disease. This regulation is characterized by increased catabolism of tryptophan to kynurenine, which was evident not only in active TB disease, but also in latent TB infection (LTBI). Further, we found that tryptophan catabolism is reversed with effective treatment of both active TB disease and LTBI in a manner commensurate with bacterial clearance. Persons with active TB and LTBI also exhibit increased expression of indoleamine 2,3-dioxygenase-1 (IDO-1), suggesting IDO-1 mediates observed increases in tryptophan catabolism. Together, these data indicate IDO-1-mediated tryptophan catabolism is highly preserved in the human response to Mycobacterium tuberculosis and could be a target for biomarker development as well as host-directed therapies.
Jeffrey M. Collins, Amnah Siddiqa, Dean P. Jones, Ken Liu, Russell R. Kempker, Azhar Nizam, N. Sarita Shah, Nazir Ismail, Samuel G. Ouma, Nestani Tukvadze, Shuzhao Li, Cheryl L. Day, Jyothi Rengarajan, James C. M. Brust, Neel R. Gandhi, Joel D. Ernst, Henry M. Blumberg, Thomas R. Ziegler
BACKGROUND. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a novel viral pneumonia (COVID-19), which is rapidly spreading in the world. The positive result of nucleic acid test is a golden criterion to confirm SARS-CoV-2 infection, but the detection features remain unclear. METHODS. We performed a retrospective analysis in 5,630 high-risk individuals receiving SARS-CoV-2 nucleic acid tests in Wuhan, China, and investigated their characteristics and diagnosis rates. RESULTS. The overall diagnosis rate was 34.7% (1,952/5,630). Male (P = 0.025) and older age (P = 2.525 × 10–39) were two significant risk factors of SARS-CoV-2 infection. People were generally susceptible, and most cases concentrated in people of 30- to 69-years-old. Besides, we investigated the association between diagnosis rate and the number of testing in 501 subjects. Results revealed a 1.27-fold improvement (35.5%/27.9%) of diagnosis rate from testing once to twice (P = 5.847 × 10–9), and a 1.43-fold improvement (39.9%/27.9%) from testing once to three times (P = 7.797 × 10–14). More than three testing times was not helpful for further improvement. However, this improvement was not observed in subjects with pneumonia (P = 0.097). CONCLUSION. All populations are susceptible to SARS-Cov-2 infection, and male and older age are two significant risk factors. Increasing the number of testing could significantly improve diagnosis rates, except for subjects with pneumonia. It is recommended to test twice in those high-risk individuals whose results are negative for the first time, and to perform three testing times is better if available.
Na Shen, Yaowu Zhu, Xiong Wang, Jing Peng, Weiyong Liu, Feng Wang, Yanjun Lu, Liming Cheng, Ziyong Sun
In severe cases of coronavirus disease 2019 (COVID-19), viral pneumonia progresses to respiratory failure. Neutrophil extracellular traps (NETs) are extracellular webs of chromatin, microbicidal proteins, and oxidant enzymes that are released by neutrophils to contain infections. However, when not properly regulated, NETs have potential to propagate inflammation and microvascular thrombosis — including in the lungs of patients with acute respiratory distress syndrome. While elevated levels of blood neutrophils predict worse outcomes in COVID-19, the role of NETs has not been investigated. We now report that sera from patients with COVID-19 (n = 50 patients, n = 84 samples) have elevated levels of cell-free DNA, myeloperoxidase(MPO)-DNA, and citrullinated histone H3 (Cit-H3); the latter two are highly specific markers of NETs. Highlighting the potential clinical relevance of these findings, cell-free DNA strongly correlated with acute phase reactants including C-reactive protein, D-dimer, and lactate dehydrogenase, as well as absolute neutrophil count. MPO-DNA associated with both cell-free DNA and absolute neutrophil count, while Cit-H3 correlated with platelet levels. Importantly, both cell-free DNA and MPO-DNA were higher in hospitalized patients receiving mechanical ventilation as compared with hospitalized patients breathing room air. Finally, sera from individuals with COVID-19 triggered NET release from control neutrophils in vitro. In summary, these data reveal high levels of NETs in many patients with COVID-19, where they may contribute to cytokine release and respiratory failure. Future studies should investigate the predictive power of circulating NETs in longitudinal cohorts, and determine the extent to which NETs may be novel therapeutic targets in severe COVID-19.
Yu Zuo, Srilakshmi Yalavarthi, Hui Shi, Kelsey Gockman, Melanie Zuo, Jacqueline A. Madison, Christopher N. Blair, Andrew Weber, Betsy J. Barnes, Mikala Egeblad, Robert J. Woods, Yogendra Kanthi, Jason S. Knight
Background: The Coronavirus Disease-2019 (COVID-19), infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a severe outbreak in China. The host immunity of COVID-19 patients is unknown. Methods: The routine laboratory tests and host immunity in COVID-19 patients with different severity of illness were compared after patient admission. Results: A total of 65 SARS-CoV-2-positive patients were classified as mild (n=30), severe (n=20), and extremely severe (n=15) illness. Many routine laboratory tests such as ferritin, lactate dehydrogenase and D-dimer were increased in severe and extremely severe patients. The absolute numbers of CD4+ T cells, CD8+ T cells and B cells were all gradually decreased with increased severity of illness. The activation markers such as HLA-DR and CD45RO expressed on CD4+ and CD8+ T cells were increased in severe and extremely severe patients compared with mild patients. The co-stimulatory molecule CD28 had opposite results. The percentage of natural regulatory T cells was decreased in extremely severe patients. The percentage of IFN-γ producing CD8+ T cells was increased in both severe and extremely severe patients compared with mild patients. The percentage of IFN-γ producing CD4+ T cells was increased in extremely severe patients. The IL-2R, IL-6, and IL-10 were all increased in extremely severe patients. The activation of DC and B cells was decreased in extremely severe patients. Conclusions: The number and function of T cells are inconsistent in COVID-19 patients. The hyperfunction of CD4+ and CD8+ T cells is associated with the pathogenesis of extremely severe SARS-CoV-2 infection.
Feng Wang, Hongyan Hou, Ying Luo, Guoxing Tang, Shiji Wu, Min Huang, Weiyong Liu, Yaowu Zhu, Qun Lin, Liyan Mao, Minghao Fang, Huilan Zhang, Ziyong Sun
Infections due to carbapenem-resistant Klebsiella pneumoniae have emerged as a global threat due to its wide-spread antimicrobial resistance. Transplant recipients and patients with hematologic malignancies have high mortality rate suggesting host factors in susceptibility. We developed a model of pulmonary infection using ST258 C4, KPC-2 clone, which are predominant Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria, and demonstrated that Rag2-/-Il2rg-/- mice, but not wildtype C57BL/6 or Rag2-/- mice, were susceptible to this opportunistic infection. Using single-cell RNA-seq in infected Rag2-/- mice, we identified distinct clusters of Ifng+ NK cells and Il17a+, Il22+, and inducible T-cell costimulatory molecule (ICOS)+ group 3 innate lymphoid cells (ILCs) that were critical for host resistance. As solid organ transplantation is a risk factor, we generated a more clinically relevant model using FK506 in wildtype C57BL/6 mice. We further demonstrated that immunotherapy with recombinant IL-22 treatment ameliorated the ST258 pulmonary infection in both FK506 treated WT mice and Rag2-/-Il2rg-/- mice via hepatic IL-22ra1 signaling. These data support the development of host directed immunotherapy as an adjunct treatment to new antibiotics.
Naoki Iwanaga, Ivy Sandquist, Alanna Wanek, Janet E. McCombs, Kejing Song, Jay Kolls
Acinetobacter baumannii is an extremely versatile multidrug resistant pathogen with a very high mortality rate therefore, it has become crucial to understand the host response during its infection. Given the importance of mice for modelling infection and their role in pre-clinical drug development equal emphasis should be placed on the utilization of both sexes. Through our studies using a murine model of acute pneumonia with A. baumannii, we observed that female mice were more susceptible to infection. Likewise, treatment of male mice with estradiol increased their susceptibility to infection. Analysis of the airway compartment revealed enhanced inflammation and reduced neutrophil and alveolar macrophage numbers compared to male mice. Depletion of either neutrophils or alveolar macrophages was important for bacterial clearance however, depletion of alveolar macrophages further exacerbated female susceptibility due to severe alterations in metabolic homoeostasis. Our data highlights the importance of utilizing both sexes when assessing host immune pathways.
Silvia Pires, Adeline C. Peignier, Jeremy Seto, Davida S. Smyth, Dane Parker
Diabetes is a significant risk factor for the development of active tuberculosis. In this study, we used a mouse model of type 2 diabetes mellitus (T2DM) to determine the effect of prior Bacillus Calmette-Guérin (BCG) vaccination on immune responses to Mycobacterium tuberculosis (Mtb) infection. We found that, at 6–7 months after Mtb infection, 90% of the Mtb-infected T2DM mice died, whereas only 50% of BCG-vaccinated T2DM-Mtb–infected mice died. Moreover, 40% of the PBS-treated uninfected T2DM mice and 30% of the uninfected BCG-vaccinated T2DM mice died, whereas all uninfected and infected nondiabetic mice survived. BCG vaccination was less effective in reducing the lung bacterial burden of Mtb-infected T2DM mice compared with Mtb-infected nondiabetic mice. BCG vaccination significantly reduced lung inflammation in Mtb-infected T2DM mice compared with that of unvaccinated T2DM mice infected with Mtb. Furthermore, reduced mortality of BCG-vaccinated Mtb-infected T2DM mice is associated with expansion of IL-13–producing CXCR3+ Tregs in the lungs of Mtb-infected T2DM mice. Recombinant IL-13 and Tregs from BCG-vaccinated Mtb-infected T2DM mice converted proinflammatory M1 macrophages to antiinflammatory M2 macrophages. Our findings suggest a potentially novel role for BCG in preventing excess inflammation and mortality in T2DM mice infected with Mtb.
Rajesh Kumar Radhakrishnan, Ramya Sivangala Thandi, Deepak Tripathi, Padmaja Paidipally, Madeline Kay McAllister, Sachin Mulik, Buka Samten, Ramakrishna Vankayalapati
Herpes simplex virus-2 (HSV-2) and HSV-1 both can cause genital herpes, a chronic infection that establishes a latent reservoir in the nervous system. Clinically, the recurrence frequency of HSV-1 genital herpes is considerably less than HSV-2 genital herpes, which correlates with reduced neuronal infection. The factors dictating the disparate outcomes of HSV-1 and HSV-2 genital herpes are unclear. In this study, we show that vaginal infection of mice with HSV-1 leads to the rapid appearance of mature DCs in the draining lymph node, which is dependent on an early burst of NK cell–mediated IFN-γ production in the vagina that occurs after HSV-1 infection but not HSV-2 infection. Rapid DC maturation after HSV-1 infection, but not HSV-2 infection, correlates with the accelerated generation of a neuroprotective T cell response and early accumulation of IFN-γ–producing T cells at the site of infection. Depletion of T cells or loss of IFN-γ receptor (IFN-γR) expression in sensory neurons both lead to a marked loss of neuroprotection only during HSV-1, recapitulating a prominent feature of HSV-2 infection. Our experiments reveal key differences in host control of neuronal HSV-1 and HSV-2 infection after genital exposure of mice, and they define parameters of a successful immune response against genital herpes.
Aisha G. Lee, Jason M. Scott, Maria Rita Fabbrizi, Xiaoping Jiang, Dorothy K. Sojka, Mark J. Miller, Megan T. Baldridge, Wayne M. Yokoyama, Haina Shin
Chikungunya virus (CHIKV) infection causes acute febrile illness in humans and some of these individuals develop a debilitating chronic arthritis that can persist for months to years for reasons that remain poorly understood. In this study from India, we characterized antibody response patterns in chikungunya febrile patients and further assessed the association of these initial febrile phase antibody response patterns with protection versus progression to developing chronic arthritis. We found five distinct patterns of the antibody responses in febrile phase: No CHIKV binding or Neutralizing (NT) antibodies but PCR positive, IgM alone with no NT activity, IgM alone with NT activity, IgM and IgG without NT activity, IgM and IgG with NT activity. A 20-month follow-up showed that appearance of NT activity regardless of antibody isotype or appearance of IgG regardless of NT activity during the initial febrile phase is associated with a robust protection against developing chronic arthritis in the future. These findings, while providing novel insights on correlates of protective immunity against chikungunya-induced chronic arthritis, suggest that qualitative differences in the antibody response patterns that have evolved during the febrile phase can serve as biomarkers, that allow prediction of protection or progression to chronic arthritis in the future.
Kaustuv Nayak, Vineet Jain, Manpreet Kaur, Naushad Khan, Kamalvishnu Gottimukkala, Charu Aggarwal, Rohit Sagar, Shipra Gupta, Ramesh Chandra Rai, Kritika Dixit, Mohammad Islamuddin, Anil Verma, Deepti Maheshwari, Yadya M. Chawla, Elluri Seetharami Reddy, Harekrushna Panda, Pragati Sharma, Priya Bhatnagar, Prabhat Singh, Siva Raghavendhar, Ashok Kumar Patel, Vinod H. Ratageri, Anmol Chandele, Pratima Ray, Kaja Murali-Krishna
Dengue (DENV) and Zika viruses (ZIKV) are closely related mosquito-borne flaviviruses that co-circulate in tropical regions and constitute major threats to global human health. Whether preexisting immunity to one virus affects disease caused by the other during primary or secondary infections is unknown but is critical in preparing for future outbreaks and predicting vaccine safety. Using a human skin explant model, we show that DENV-3 immune sera increased recruitment and infection of Langerhans cells, macrophages and dermal dendritic cells following inoculation with DENV-2 or ZIKV. Similarly, ZIKV immune sera enhanced infection with DENV-2. Immune sera increased migration of infected Langerhans cells to dermis and emigration of infected cells out of skin. Heterotypic immune sera increased viral RNA in dermis almost tenfold and reduced the amount of virus required to infect a majority of myeloid cells by 100 to 1,000 fold. Enhancement was associated with cross-reactive IgG and induction of IL-10 expression and was mediated by both CD32 and CD64 Fcγ receptors. These findings reveal that preexisting heterotypic immunity greatly enhances DENV and ZIKV infection, replication and spread in human skin. This relevant tissue model will be valuable in assessing the efficacy and risk of dengue and Zika vaccines in humans.
Priscila M.S. Castanha, Geza Erdos, Simon C. Watkins, Louis D. Falo, Jr., Ernesto T.A. Marques, Simon M. Barratt-Boyes
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